News beyond our pages
Authors: Marc E. Rothenberg, Jean Bousquet
Journal: Journal of Allergy and Clinical Immunology (2023)

Tezepelumab, which inhibits thymic stromal lymphopoietin, demonstrated efficacy in the phase 2 PATHWAY and phase 3 NAVIGATOR randomized, placebo-controlled clinical trials in diverse subgroups of patients with severe asthma as defined by baseline peripheral eosinophil counts and fractional exhaled nitric oxide (Feno) levels. Corren et al (Am J Respir Crit Care Med 2023 Apr 4; https://doi.org/10.1164/rccm.202210-2005OC) performed a post hoc pooled analysis of these 2 studies to examine the efficacy of tezepelumab in additional subgroups. Notably, tezepelumab decreased exacerbation frequency and rate of exacerbation-related emergency department visit or hospitalization in subjects regardless of type 2 inflammation status or clinical characteristics such as presence of perennial aeroallergen sensitivity and exacerbation history. The findings from this analysis support expanding the use of tezepelumab in asthma beyond type 2-high disease. Image attribution BruceBlaus, CC BY-SA 4.0 https://creativecommons.org/licenses/by-sa/4.0, via Wikimedia Commons.Regardless of type 2 inflammation status Regardless of type 2 inflammation status Overactivation of group 2 innate lymphoid cells (ILC2s) that express T cell immunoreceptor with Ig and ITIM domains (TIGIT) have been identified in chronic airway allergy. Yamada et al (J Exp Med 2023;220:e20222005; https://doi.org/10.1084/jem.20222005) utilized TIGIT lineage tracer mice to clarify the physiologic relevance of this cellular population. During chronic airway allergic inflammation, TIGIT-expressing ILC2s were highly activated and exhibited short life spans due to apoptosis mediated by CD155-expressing alveolar macrophages. Notably, both genetic ablation of Tigit and treatment with exogenous anti-TIGIT blocking antibodies enhanced ILC2 survival to aggravate chronic allergic inflammation. Collectively, these results identify that TIGIT mediates activation-induced cell death of ILC2s to alleviate chronic allergic inflammation. Image attribution NIH Image Gallery from Bethesda, Maryland, USA, Public domain, via Wikimedia Commons. We asked corresponding author Takashi Ebihara, MD, PhD, of the Akita University Graduate School of Medicine, Akita, Japan, to comment on the study. He writes, “ILC2s have been believed to be very ‘tough’ cells working for chronic allergy at tissues, as evidenced by unlimited proliferation of activated ILC2s in vitro. We found that activation-induced cell death of ILC2s is perpetually induced by the interaction with macrophages when ILC2s express TIGIT during chronic airway allergy to suppress overwhelming inflammation.” Allinson et al (Lancet 2023;401(10383):1183-93; https://doi.org/10.1016/S0140-6736(23)00131-9) assessed the relation between early life lower respiratory tract infections (LRTIs) and adult premature death from respiratory disease through a prospective national birth cohort study in Great Britain involving over 5000 subjects. Even after adjustment for socioeconomic and adult smoking status, LRTIs during the first 2 years of life almost doubled the risk of respiratory disease-related death during adulthood and accounted for approximately twenty percent of adult deaths from respiratory disease. Notably, early childhood LRTIs did not affect the risk of nonrespiratory causes of death. Collectively, these findings suggest that early childhood LRTIs increase the risk of premature adult death from respiratory disease. We asked corresponding author James Allinson, PhD, MD, of the National Heart and Lung Institute, Imperial College London, London, United Kingdom, to comment on the study. He writes, “Linking 1 in 5 adult respiratory deaths to common early childhood infection shows the need to target risk well before adulthood. To prevent the perpetuation of existing adult health inequalities we need to optimize childhood health, not least by tackling childhood poverty, and showing the early life origins of adult chronic diseases also helps challenge the smoking-related stigma attached to death from diseases such as COPD.” Hallmarks of IgE-mediated anaphylaxis include precipitous hypotension in humans and decreased core body temperature in mice. Bao et al (Sci Immunol 2023;8:eadc9417; https://doi.org/10.1126/sciimmunol.adc9417) identified that anaphylaxis-induced drops in core body temperature in mice involve improper activation of the body’s nervous system, especially the thermoregulatory neural circuit. More specifically, mast cell-derived chymase activated TRPV1-expressing sensory neurons by binding the extracellular receptor protease-activated receptor-1 (PAR1). The subsequent inappropriate activation of the warm thermoregulatory neural circuit then induced hypothermia by inhibiting thermogenesis of brown adipose tissue. Experimental murine studies revealed that genetic deficiency of either chymase or TRPV1 limited IgE-mediated anaphylaxis. In total, these results illustrate the improper activation of the thermoregulatory neural circuit in IgE-mediated anaphylaxis and support further investigation into inhibition of the mast cell-sensory neuron-central nervous system axis to prevent anaphylaxis.Chunjing Bao and Soman AbrahamView Large Image Figure ViewerDownload Hi-res image Download (PPT) We asked first author, Chunjing Bao, PhD, and corresponding author Soman Abraham, PhD, both of the Department of Pathology, Duke University Medical Center, Durham, North Carolina, to comment on the study. They write, “This study is the first to demonstrate that, in addition to the well-established impact of mast cells on the vasculature (causing plasma leakage and vasodilation), the nervous system also plays a critical role in the pathogenesis of anaphylaxis. The intricate interplay between the immune and nervous systems uncovered in this study provides us with new targets for novel therapeutic approaches to manage anaphylaxis.” Chen et al (Science 2023;380:203-10; https://doi.org/10.1126/science.abp9563) generated tumor-specific T cells by genetically engineering the skin bacterium Staphylococcus epidermidis to express melanoma tumor antigens bound to either secreted or cell-surface proteins. After skin colonization, this engineered S epidermidis induced circulating tumor-specific T cells with antitumor cytotoxic activity in both local and metastatic melanoma lesions. Collectively, these findings identify that commensal skin bacteria license tumor-specific T cells capable of infiltrating tumors and exerting cytotoxic effects and raise the possibility of inducing highly specific T-cell responses at distal sites by engineering antigen expression in commensal bacteria.Antitumor cytotoxic activity in both local and metastatic melanoma lesionsNews items were written by medical writer Jared Travers, MD, PhD. Antitumor cytotoxic activity in both local and metastatic melanoma lesions News items were written by medical writer Jared Travers, MD, PhD.